bMeiji University International Institute for Bio-Resource Research, Kawasaki 214-8571, Japan;cLaboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan;

aDivision of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan;eDivision of Regenerative Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan;

bMeiji University International Institute for Bio-Resource Research, Kawasaki 214-8571, Japan;cLaboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan;

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Significance

Worldwide, the number of patients with end-stage renal disease requiring renal replacement therapy is increasing because of the shortage of donor organs. We have successfully generated functional kidneys from human stem cells using the organogenic niche method. However, for these kidneys to have clinical application, a urinary excretion pathway is necessary. Using pigs, we demonstrated our stepwise peristaltic ureter system, showing that it resolves important problems regarding the construction of the urine excretion pathway and the long-term growth of the stem cell-generated embryonic kidneys.

Abstract

There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney. First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal’s ureter to the cloacal-developed bladder, a technique we called the “stepwise peristaltic ureter” (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter. Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney.

Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.